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Necrotizing glomerulonephritis in a living donor kidney transplant recipient
Necrotizing Glomerulonephritis in a Living Donor Kidney Transplant Recipient M. Campise, A. Tarantino, G. Banfi, and C. Ponticelli ABSTRACT The occurrence of a rapidly progressive necrotizing glomerulonephritis after kidney transplantation is exceptional and usually leads to graft failure. We describe a case of necrotizing glomerulonephritis that developed 5 months after renal transplantation in a patient suffering from prolonged bowel paralysis and sepsis. After reinforcement of corticosteroid therapy and introduction of cyclophosphamide, glomerulonephritis recovered. Cyclophosphamide was stopped after 2 months and replaced by azatioprine while prednisone was progressively reduced. Three years after transplantation the patient has a stable serum creatinine of 1.7 mg/dL and mild proteinuria. To the best of our knowledge this is the first case of recovery from a necrotizing glomerulonephritis in a renal transplant recipient.
D
E NOVO GLOMERULONEPHRITIS is a rare complication of renal transplantation. Membranous nephropathy1 and hepatitis C-related membranoproliferative glomerulonephritis2 are the most frequent types of de novo glomerulonephritis. These diseases, which usually become manifest months or years after renal transplantation, are often associated with poor long-term graft survival.3 Exceptionally, cases of necrotizing paucimmune glomerulonephritis with rapid progression to end-stage renal failure have also been reported in renal allograft recipients.4,5 Here we report another case of a de novo necrotizing glomerulonephritis that occurred a few months after transplantation in a patient who had an extremely prolonged bowel paralysis followed by sepsis. However, in contrast to the previous cases, the graft function recovered. The renal transplant is still working after more than 3 years. CASE REPORT A 57-year-old man was referred to our unit for a living donor kidney transplantation from his HLA-haploidentical sister aged 52 years. In 1983 he was discovered to have hypertension and chronic renal failure. No renal biopsy was performed. In March 1995, he was submitted to peritoneal dialysis. His past medical history was remarkable save for a selective vagotomy and pyloroplasty because of a peptic ulcer in 1981, and an acute myocardial infarction followed by coronary revascularization in October 1995. The patient was also hepatitis B virus (HBV)- and HBV DNA-positive, but his liver function tests remained normal at the time of transplant. The transplant was performed from his sister in September 1999. The immunosuppression included intravenous basiliximab (20 mg 0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00381-6 1368
on day 0 and 4), neoral (4 mg/kg/d), mycophenolate mofetil (MMF; 2 g per day), and intravenous methylprednisolone at decreasing doses over 5 days from 125 mg to 20 mg/d followed by complete withdrawal. After transplantation, renal function promptly recovered, the serum creatinine fell to 1.4 mg/dL within 6 days. Eight days after surgery the patient developed gastric pain and diarrhea, which were initially attributed to MMF. This drug was replaced with azathioprine (75 mg per day), but the abdominal symptoms worsened, leading to complete bowel paralysis. In the meantime he displayed progressively more severe liver dysfunction with the serum ALT increasing from 50 to 150 IU/L, serum AST from 32 to 80 IU/L, and total bilirubin from 0.6 mg/dL to 8.0 mg/dL, while the cholinesterase fell from 5420 to 839 IU/L. An exploratory laparatomy revealed the intestinal wall to be thickened but there was no evidence of obstruction. Peritoneal biopsy failed to show sclerosing peritonitis. A few days later the patient developed a wound infection with chills and fever to 40°C and the onset of hypertension. After Staphylococcus epidermidis was isolated from the blood, vancomycin and imipenem-cylastatin was administered. Nevertheless, liver dysfunction and bowel paralysis persisted necessitating total parenteral nutrition and large doses of prostigmine. The serum creatinine remained stable (1.3 mg/dL) on immunosuppression monotherapy with intravenous cyclosporine (60 mg/dL). The liver function tests began to improve in December From the Divisione di Nefrologia, IRCCS Ospedale Maggiore, Milano, Italy. Supported by a grant “Project glomerulonephritis” in memory of Pippo Neglia. Address reprint requests to Mariarosaria Campise, MD, Divisione di Nefrologia IRCCS Ospedale Maggiore, Via Commenda, 15 20122 Milano, Italy. E-mail: [email protected] © 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35, 1368-1369 (2003)
NECROTIZING GLOMERULONEPHRITIS 1999. Despite persistent bowel paralysis, nutrition was slowly reintroduced. The fever disappeared at the beginning of January 2000, after prolonged treatment with vancomicin, teicoplanine, and ceftriaxone. Bowel activity reappeared in mid January with a progressive normalization of intestinal function. However, at the end of January he developed nephrotic range proteinuria (more than 7 g/d), hematuria, severe hypertension (180/110 to 115 mm Hg) and a progressive increasing serum creatinine (up to 4.5 mg/dL). Serum levels of C3 (102 mg/dL) and C4 (27 mg/dL) were normal, P and C ANCA were negative. Because an echo doppler of the transplanted kidney showed a tight arterial stenosis, he underwent transluminal angioplasty and the placement of a stent. After resolution of the stenosis, the blood pressure improved, but the serum creatinine and the proteinuria did not change. On renal biopsy the light microscopy revealed circumferential extracapillary proliferation with glomerular tuft collapse in 7 among 16 glomeruli. In some glomeruli fibrinoid necrosis was associated with polymorphonuclear granulocytes. In other preserved glomeruli, protein deposits were observed in mesangial and paramesangial positions. The interstitium displayed slight fibrosis with scattered infiltration of mononuclear cells. Some tubular areas showed severe epithelial damage associated with aggregates of intraluminal erythrocytes. Immunofluorescence examination showed fibrinogen deposits in the areas with fibrinoid necrosis, as well as scanty mesangial deposits of C3 and IgA. Electron microscopy confirmed the picture of extracapillary glomerulonephritis with fibrin exudation into Bowman’s space, while the few glomeruli examined did not demonstrate clear-cut osmiophilic deposits. These findings established a diagnosis of extracapillary necrotizing glomerulonephritis. Cyclosporine was stopped; the patient was treated with intravenous methylprednisolone 500 mg per day for 3 consecutive days followed by oral cyclophosphamide 50 mg per day for 2 months and prednisone 25 mg per day for 2 months, which was then tapered to 15 mg per day. Two months later the patient was changed to azatioprine (125 mg/d) together with prednisone 15 mg per day. He was discharged on 28 March 2000. In September 2000, a second renal biopsy showed only focal and segmental glomerular scarring. A liver biopsy was performed in October 2000 and showed mild chronic HBV hepatitis. At the last follow-up visit (Jannuary 3, 2003) the patient was in good health condition and had returned to normal life. His serum creatinine was 1.7 mg/dL and proteinuria 0.33 g per day. Liver enzyme tests were mildly increased, but cholinesterase as well as total protein and albumin were normal. HBV DNA was positive at high titer: 909 mEq/L.
DISCUSSION
This patient developed severe and long-lasting sepsis as a consequence of a Staphylococcus epidermitis wound infection. Infection was certainly favored by his poor general condition caused by the extremely prolonged bowel paralysis and consequent malnutrition. To the best of our knowledge, no case with such a prolonged, but reversible, bowel paralysis has been previously reported in a renal transplant recipient. Bowel activity began only 4 months after continuous and massive doses of prostigmine and slow
1369
reintroduction of oral nutrition. A few months after transplantation, the patient developed severe necrotizing extracapillary glomerulonephritis with rapidly progressive renal failure, nephrotic syndrome, and arterial hypertension. Usually this rare complication is triggered by bacterial infections6 or by association with ANCA. In our patient the association with sepsis and the presence of a large number of polymorphonuclear cells together with scanty but clearcut deposits of immunoglobulins and C3 at renal biopsy, strongly suggest that the rapidly progressive glomerulonephritis was triggered by infection. This association was first reported in patients with infective endocarditis.7 Those patients displayed various histological patterns, such as mesangial or membranoproliferative, extracapillary crescentic, or a combination of endo- and extracapillary glomerulonephritis. As in our case an interstitial infiltrate of inflammatory cells is frequently associated with necrotizing glomerulonephritis. The histological pattern may depend on the duration of infection8 and the possibility of recovery is strictly dependent on the cause leading to acute renal failure.9 In our patient the discovery of an acute crescentic glomerulonephritis led to the prompt institution of corticosteroids and cytotoxic therapy with a good final result. Two cases of necrotizing glomerulonephritis in renal transplant recipients have previously been reported4,5 but both patients eventually lost the kidney allograft. We speculate that the better outcome in our patient was related to the resolution of infection and to the specific immunosuppressive therapy. Although a rare complication, the possibility of acute necrotizing glomerulonephritis should be kept in mind in transplanted patient. Even if it is difficult to draw conclusions from the experience of a single case, we feel that following resolution of an infection, prompt institution of high-dose corticosteroids and cyclophosphamide may favor remission in such cases. REFERENCES 1. Schwarz A, Krause PH, Offerman G, et al: Transplantation 58:650, 1994 2. Cruzado JM, Carrera M, Torras J, et al: Am J Transplant 1:171, 2001 3. Hariharan S, Adams MB, Brennan DC, et al: Transplantation 68:635, 1999 4. Diaz-Tejero R, Maduell F, Diez J, et al: Nephron 54:341, 1990 5. Lucas F: Transplant Proc 26:3693, 1994 6. Jones B, Trevillian P, Hibberd A, et al: Am J Kidney Dis 16:501, 1990 7. Keslin MH, Messner RP, Williams RC Jr: Arch Intern Med 132:578, 1973 8. Beaufils M, Morel Maroger L, et al: N Engl J Med 295:185, 1976 9. Beaufils M: Kidney Int 19:609, 1981
D
E NOVO GLOMERULONEPHRITIS is a rare complication of renal transplantation. Membranous nephropathy1 and hepatitis C-related membranoproliferative glomerulonephritis2 are the most frequent types of de novo glomerulonephritis. These diseases, which usually become manifest months or years after renal transplantation, are often associated with poor long-term graft survival.3 Exceptionally, cases of necrotizing paucimmune glomerulonephritis with rapid progression to end-stage renal failure have also been reported in renal allograft recipients.4,5 Here we report another case of a de novo necrotizing glomerulonephritis that occurred a few months after transplantation in a patient who had an extremely prolonged bowel paralysis followed by sepsis. However, in contrast to the previous cases, the graft function recovered. The renal transplant is still working after more than 3 years. CASE REPORT A 57-year-old man was referred to our unit for a living donor kidney transplantation from his HLA-haploidentical sister aged 52 years. In 1983 he was discovered to have hypertension and chronic renal failure. No renal biopsy was performed. In March 1995, he was submitted to peritoneal dialysis. His past medical history was remarkable save for a selective vagotomy and pyloroplasty because of a peptic ulcer in 1981, and an acute myocardial infarction followed by coronary revascularization in October 1995. The patient was also hepatitis B virus (HBV)- and HBV DNA-positive, but his liver function tests remained normal at the time of transplant. The transplant was performed from his sister in September 1999. The immunosuppression included intravenous basiliximab (20 mg 0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00381-6 1368
on day 0 and 4), neoral (4 mg/kg/d), mycophenolate mofetil (MMF; 2 g per day), and intravenous methylprednisolone at decreasing doses over 5 days from 125 mg to 20 mg/d followed by complete withdrawal. After transplantation, renal function promptly recovered, the serum creatinine fell to 1.4 mg/dL within 6 days. Eight days after surgery the patient developed gastric pain and diarrhea, which were initially attributed to MMF. This drug was replaced with azathioprine (75 mg per day), but the abdominal symptoms worsened, leading to complete bowel paralysis. In the meantime he displayed progressively more severe liver dysfunction with the serum ALT increasing from 50 to 150 IU/L, serum AST from 32 to 80 IU/L, and total bilirubin from 0.6 mg/dL to 8.0 mg/dL, while the cholinesterase fell from 5420 to 839 IU/L. An exploratory laparatomy revealed the intestinal wall to be thickened but there was no evidence of obstruction. Peritoneal biopsy failed to show sclerosing peritonitis. A few days later the patient developed a wound infection with chills and fever to 40°C and the onset of hypertension. After Staphylococcus epidermidis was isolated from the blood, vancomycin and imipenem-cylastatin was administered. Nevertheless, liver dysfunction and bowel paralysis persisted necessitating total parenteral nutrition and large doses of prostigmine. The serum creatinine remained stable (1.3 mg/dL) on immunosuppression monotherapy with intravenous cyclosporine (60 mg/dL). The liver function tests began to improve in December From the Divisione di Nefrologia, IRCCS Ospedale Maggiore, Milano, Italy. Supported by a grant “Project glomerulonephritis” in memory of Pippo Neglia. Address reprint requests to Mariarosaria Campise, MD, Divisione di Nefrologia IRCCS Ospedale Maggiore, Via Commenda, 15 20122 Milano, Italy. E-mail: [email protected] © 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35, 1368-1369 (2003)
NECROTIZING GLOMERULONEPHRITIS 1999. Despite persistent bowel paralysis, nutrition was slowly reintroduced. The fever disappeared at the beginning of January 2000, after prolonged treatment with vancomicin, teicoplanine, and ceftriaxone. Bowel activity reappeared in mid January with a progressive normalization of intestinal function. However, at the end of January he developed nephrotic range proteinuria (more than 7 g/d), hematuria, severe hypertension (180/110 to 115 mm Hg) and a progressive increasing serum creatinine (up to 4.5 mg/dL). Serum levels of C3 (102 mg/dL) and C4 (27 mg/dL) were normal, P and C ANCA were negative. Because an echo doppler of the transplanted kidney showed a tight arterial stenosis, he underwent transluminal angioplasty and the placement of a stent. After resolution of the stenosis, the blood pressure improved, but the serum creatinine and the proteinuria did not change. On renal biopsy the light microscopy revealed circumferential extracapillary proliferation with glomerular tuft collapse in 7 among 16 glomeruli. In some glomeruli fibrinoid necrosis was associated with polymorphonuclear granulocytes. In other preserved glomeruli, protein deposits were observed in mesangial and paramesangial positions. The interstitium displayed slight fibrosis with scattered infiltration of mononuclear cells. Some tubular areas showed severe epithelial damage associated with aggregates of intraluminal erythrocytes. Immunofluorescence examination showed fibrinogen deposits in the areas with fibrinoid necrosis, as well as scanty mesangial deposits of C3 and IgA. Electron microscopy confirmed the picture of extracapillary glomerulonephritis with fibrin exudation into Bowman’s space, while the few glomeruli examined did not demonstrate clear-cut osmiophilic deposits. These findings established a diagnosis of extracapillary necrotizing glomerulonephritis. Cyclosporine was stopped; the patient was treated with intravenous methylprednisolone 500 mg per day for 3 consecutive days followed by oral cyclophosphamide 50 mg per day for 2 months and prednisone 25 mg per day for 2 months, which was then tapered to 15 mg per day. Two months later the patient was changed to azatioprine (125 mg/d) together with prednisone 15 mg per day. He was discharged on 28 March 2000. In September 2000, a second renal biopsy showed only focal and segmental glomerular scarring. A liver biopsy was performed in October 2000 and showed mild chronic HBV hepatitis. At the last follow-up visit (Jannuary 3, 2003) the patient was in good health condition and had returned to normal life. His serum creatinine was 1.7 mg/dL and proteinuria 0.33 g per day. Liver enzyme tests were mildly increased, but cholinesterase as well as total protein and albumin were normal. HBV DNA was positive at high titer: 909 mEq/L.
DISCUSSION
This patient developed severe and long-lasting sepsis as a consequence of a Staphylococcus epidermitis wound infection. Infection was certainly favored by his poor general condition caused by the extremely prolonged bowel paralysis and consequent malnutrition. To the best of our knowledge, no case with such a prolonged, but reversible, bowel paralysis has been previously reported in a renal transplant recipient. Bowel activity began only 4 months after continuous and massive doses of prostigmine and slow
1369
reintroduction of oral nutrition. A few months after transplantation, the patient developed severe necrotizing extracapillary glomerulonephritis with rapidly progressive renal failure, nephrotic syndrome, and arterial hypertension. Usually this rare complication is triggered by bacterial infections6 or by association with ANCA. In our patient the association with sepsis and the presence of a large number of polymorphonuclear cells together with scanty but clearcut deposits of immunoglobulins and C3 at renal biopsy, strongly suggest that the rapidly progressive glomerulonephritis was triggered by infection. This association was first reported in patients with infective endocarditis.7 Those patients displayed various histological patterns, such as mesangial or membranoproliferative, extracapillary crescentic, or a combination of endo- and extracapillary glomerulonephritis. As in our case an interstitial infiltrate of inflammatory cells is frequently associated with necrotizing glomerulonephritis. The histological pattern may depend on the duration of infection8 and the possibility of recovery is strictly dependent on the cause leading to acute renal failure.9 In our patient the discovery of an acute crescentic glomerulonephritis led to the prompt institution of corticosteroids and cytotoxic therapy with a good final result. Two cases of necrotizing glomerulonephritis in renal transplant recipients have previously been reported4,5 but both patients eventually lost the kidney allograft. We speculate that the better outcome in our patient was related to the resolution of infection and to the specific immunosuppressive therapy. Although a rare complication, the possibility of acute necrotizing glomerulonephritis should be kept in mind in transplanted patient. Even if it is difficult to draw conclusions from the experience of a single case, we feel that following resolution of an infection, prompt institution of high-dose corticosteroids and cyclophosphamide may favor remission in such cases. REFERENCES 1. Schwarz A, Krause PH, Offerman G, et al: Transplantation 58:650, 1994 2. Cruzado JM, Carrera M, Torras J, et al: Am J Transplant 1:171, 2001 3. Hariharan S, Adams MB, Brennan DC, et al: Transplantation 68:635, 1999 4. Diaz-Tejero R, Maduell F, Diez J, et al: Nephron 54:341, 1990 5. Lucas F: Transplant Proc 26:3693, 1994 6. Jones B, Trevillian P, Hibberd A, et al: Am J Kidney Dis 16:501, 1990 7. Keslin MH, Messner RP, Williams RC Jr: Arch Intern Med 132:578, 1973 8. Beaufils M, Morel Maroger L, et al: N Engl J Med 295:185, 1976 9. Beaufils M: Kidney Int 19:609, 1981